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Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis
T R Devereux1, C H Anna, J F Foley
1Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, North Carolina, NC 27709, USA.
Abstract:
beta-catenin activation, and subsequent upregulation of Wnt-signaling, is an important event in the development of certain human and rodent cancers. Recently, mutations in the beta-catenin gene in the region of the serine-threonine glycogen kinase (GSK)-3beta phosphorylation target sites have been identified in hepatocellular neoplasms from humans and transgenic mice. In this study we examined 152 hepatocellular neoplasms from B6C3F1 mice included in five chemical treatment groups and controls for mutations in the beta-catenin gene. Twenty of 29 hepatocellular neoplasms from mice treated with methyleugenol had point mutations at codons 32, 33, 34 or 41, sites which are mutated in colon and other cancers. Likewise, nine of 24 methylene chloride-induced hepatocellular neoplasms and 18 of 42 oxazepam-induced neoplasms exhibited similar mutations. In contrast, only three of 18 vinyl carbamate-induced liver tumors, one of 18 TCDD-induced liver tumors, and two of 22 spontaneous liver neoplasms had mutations in beta-catenin. Thus, there appears to be a chemical specific involvement of beta-catenin activation in mouse hepatocellular carcinogenesis. Expression analyses using Western blot and immunohistochemistry indicate that beta-catenin protein accumulates along cell membranes following mutation. The finding of mutations in both adenomas and carcinomas from diverse chemical treatment groups and the immunostaining of beta-catenin protein in an altered hepatocellular focus suggest that these alterations are early events in mouse hepatocellular carcinogenesis.
Insights
Chemicals like methyleugenol, methylene chloride, and oxazepam activate beta-catenin, a key protein in Wnt-signaling, promoting liver cancer development in mice. These mutations appear to be early events in carcinogenesis.
Area of Science:
- Hepatocellular Carcinogenesis
- Molecular Biology
- Toxicology
Background:
- Beta-catenin activation and Wnt-signaling are crucial in various cancers.
- Mutations in the beta-catenin gene, particularly at GSK-3beta phosphorylation sites, are implicated in hepatocellular neoplasms.
- Understanding these mutations is key to identifying early events in liver cancer development.
Purpose of the Study:
- To investigate mutations in the beta-catenin gene in hepatocellular neoplasms from B6C3F1 mice exposed to different chemicals.
- To determine the chemical-specific involvement of beta-catenin activation in mouse liver carcinogenesis.
- To assess whether beta-catenin alterations are early events in hepatocellular carcinogenesis.
Main Methods:
- Analysis of 152 hepatocellular neoplasms from B6C3F1 mice across five chemical treatment groups and controls.
- Sequencing of the beta-catenin gene to identify point mutations at specific codons (32, 33, 34, 41).
- Western blot and immunohistochemistry to analyze beta-catenin protein expression and localization.
Main Results:
- Significant point mutations in beta-catenin were found in neoplasms from mice treated with methyleugenol (20/29), methylene chloride (9/24), and oxazepam (18/42).
- Fewer mutations were observed in liver tumors induced by vinyl carbamate (3/18), TCDD (1/18), and spontaneous neoplasms (2/22).
- Beta-catenin protein accumulation along cell membranes was observed following mutations, indicated by Western blot and immunohistochemistry.
Conclusions:
- Beta-catenin activation shows chemical-specific involvement in mouse hepatocellular carcinogenesis.
- Mutations in beta-catenin occur in both adenomas and carcinomas, suggesting they are early events.
- Altered beta-catenin expression and localization are associated with early stages of liver cancer development in mice.